Temp-Prevent

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitair Medisch Centrum Utrecht

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14], Diseases [C] - Eye Diseases [C11], Diseases [C] - Skin and Connective Tissue Diseases [C17]

Trial duration

26 Apr 2023 → ongoing

Decision date (initial)

2024-10-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Stichting PXE-fonds · Oogvereniging · Oogfonds · Stichting Dioraphte

External identifiers

EU CT number

2024-512133-33-00

EudraCT number

2021-000434-34

ClinicalTrials.gov

NCT05832580

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

To determine if 24 months of treatment with etidronate halts the progression of arterial calcification in the legs and carotid siphons.

Secondary objectives 11

1. To determine the effect of 24 months of treatment with etidronate on functional ophthalmological measurements, such as visual acuity and contrast sensitivity compared to placebo.
2. To determine if 24 months of treatment with etidronate halts the progression of normalized reflectivity in Bruch’s membrane as measured with SD-optical coherence tomography, compared to placebo.
3. To determine the effect of 24 months of treatment with etidronate on structural ophthalmological measurements, on fundus photography, (infrared (IR) and autofluorescence (FAF)) and OCT-angiography (OCTA).
4. To determine if 24 months of treatment with etidronate affects the intracranial velocity pulsatility index as measured with MRI.
5. To determine if 24 months of treatment with etidronate halts the progression of elastin degradation and of calcification in the skin in dermatological observation of skin biopsies, compared to placebo.
6. To determine the effect of 24 months of treatment with etidronate on inorganic pyrophosphate an desmosine compared to placebo.
7. To determine if 24 months of treatment with etidronate halts leads to changes in vascular measurements (carotid intima-media thickness, pulse wave velocity on ultrasound, ankle brachial index, 6 minute walking test and WELCH questionnaire) compared to placebo.
8. To determine if 24 months of treatment with etidronate leads to decreased occurrence of major adverse cardiovascular events (stroke, TIA, myocardial infarction or cardiovascular death) compared to placebo.
9. To determine if 24 months of treatment with etidronate leads to improved reported quality of life and self-reported health, as measured with the EQ-5D, PROMIS 10, PROMIS PF en USER P, compared to placebo.
10. To determine if 24 months of treatment with etidronate leads to better results on cognitive outcomes, compared with placebo.
11. To determine if 24 months of treatment with etidronate leads to observed differences in safety measures: changes in plasma calcium, phosphate measured via laboratory assessment, and number of anti-VEGF injections used.

Conditions and MedDRA coding

Pseudoxanthoma Elasticum

Regulatory references

Scientific advice from competent authorities

Central Committee On Research Involving Human Subjects, METC Utrecht

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

1. Be between 18 years and 55 years
2. Have a definitive diagnosis of PXE according to the Plomp criteria27, which confirm a diagnosis of PXE when at least two (or more) criteria not belonging to the same category (skin, eye, genetic) are met: 1. Skin a. Yellowish papules and/or plaques on the lateral side of the neck and/or flexural areas of the body or b. Increase of morphologically altered elastin with fragmentation, clumping and calcification of elastic fibers in a skin biopsy taken. 2. Eye a. Peau d'orange of the retina or b. One or more angioid streaks (AS), each at least as long as one disk diameter. When in doubt, fluorescein or indocyanine green angiography of the fundus is needed for confirmation. 3. Genetics a. A pathogenic mutation of both alleles of the ABCC6 gene or b. A first-degree relative (parent, sibling or child) who meets independently the diagnostic criteria for definitive PXE
3. Fertile women must take adequate anticonception.

Exclusion criteria 11

1. Patients that are unable or unwilling to sign for informed consent.
2. Pregnant, lactating, or fertile women who might wish to become pregnant within three years.
3. Patients with an estimated glomerular filtration rate below 30 ml/min/1.73m2 according to the CKD-EPI equation
4. Patients with a known abnormality of the oesophagus that would interfere with passage of the drug (e.g. oesophagus stenosis).
5. Patients with chronic diarrhoea (> 1 month).
6. Patients with known osteomalacia;
7. Patients with hypocalcaemia (calcium <2.20 mmol/L corrected for albumin)*. *After correction a patient is again suitable for participation, as long as inclusion criteria are met
8. Patients with a vitamin D deficiency (<35 nmol/L)*. *After correction a patient is again suitable for participation, as long as inclusion criteria are met
9. Patients that used a bisphosphonate in the last 5 years.
10. Patients with known sensitivity to etidronate.
11. Any other medical or social condition that, at the discretion of the Principal Investigator, might put the subject at risk of harm during the study or might adversely affect the interpretation of the study data.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The main study endpoint will be the percentage change in arterial calcification in carotid siphon and legs measured with low-dose CT scan after 24 months of treatment with etidronate compared with placebo.

Secondary endpoints 15

1. To determine the effect of 24 months of treatment with etidronate on functional ophthalmological measurements, such as visual compared to placebo.
2. To determine if 24 months of treatment with etidronate halts the progression of normalized reflectivity in Bruch’s membrane as measured with SD-optical coherence tomography, compared to placebo.
3. To determine the effect of 24 months of treatment with etidronate on structural ophthalmological measurements on fundus photography (infrared and autofluorescence and OCT-angiography).
4. 7T Magnetic resonance imaging will be used to determine if treatment with etidronate halts the progression of increased pulsatility index of the intracranial carotid arteries and middle cerebral arteries.
5. To determine if treatment with etidronate halts the progression of elastin degradation and of calcification in the skin in skin biopsies, compared to placebo.
6. To determine if treatment with etidronate leads to increased levels of plasma levels of inorganic pyrophosphate compared to placebo.
7. To determine if treatment with etidronate halts the progression of systemic elastin degradation products, as measured via plasma levels of desmosin, compared to placebo.
8. To determine if treatment with etidronate halts the progression of arterial calcification in legs and siphons, as measured with computed tomography, compared to placebo.
9. To determine if treatment with etidronate halts the progression of increased carotid intima media thickness, as measured with ultrasound with a linear array transducer, compared to placebo.
10. To determine if treatment with etidronate halts the progression of arterial stiffness, as measured by pulse wave analysis and velocity using a Doppler-ultrasound, compared to placebo.
11. To determine if treatment with etidronate halts progression of peripheral artery disease measured by the ankle brachial index, the WELCH questionnaire and the six-minute walking test.
12. To determine if treatment with etidronate leads to decreased occurrence of major cardiovascular events (stroke, TIA, myocardial infarction or cardiovascular death) events compared to placebo.
13. To determine if treatment with etidronate leads to improved reported quality of life and self reported health, as measured with the EQ-5D, PROMIS 10, PROMIS PF, USER P compared to placebo.
14. To determine if 24 months of treatment with etidronate leads to better results on cognitive outcomes, compared with placebo
15. To determine if treatment with etidronate leads to observed differences in safety measures: changes in plasma calcium, phosphate, ASAT, ALAT, eGFR measured via laboratory assessment, and number of anti-VEGF injections used

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitair Medisch Centrum Utrecht

Sponsor organisation

Universitair Medisch Centrum Utrecht

Address

Heidelberglaan 100

City

Utrecht

Postcode

3584 CX

Country

Netherlands

Scientific contact point

Organisation

Universitair Medisch Centrum Utrecht

Contact name

Wilko Spiering

Public contact point

Organisation

Universitair Medisch Centrum Utrecht

Contact name

Wilko Spiering

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 4 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications